Biennial Review of Pain
The brain on opioids
Jane C. Ballantyne
1. Introduction
There is some logic to having acute pain. It acts as a signal for
withdrawal from danger or damage; it enforces rest after injury or
during illness; and it can be used in pain vs pleasure calculations
of which signals are needed to avert future damage or incite
Downloaded from https://journals.lww.com/pain by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3GqhOzspyl8wL8wQ+YeBcbAlsFu0qDXKTFcZfMblYgrM= on 10/13/2018
beneficial behaviors. Chronic pain, on the other hand, seems to
have no purpose. In fact, the more we learn about pain
processes, the clearer it becomes that chronic pain differs from
acute pain in ways not previously appreciated. It may be felt
similarly in that it is perceived in an anatomical location, often after
an acute injury or event. It is easy to assume that chronic pain is
merely acute pain that has not gone away, and reflects
unresolved peripheral damage. Yet, recent scientific study has
revealed processes in the nervous system, and particularly the
brain, which account for chronic pain, and are distinct from acute
pain processes. A seemingly paradoxical role for the endogenous
opioid system in the development of chronic pain is brought to
light. What follows is that the actions of exogenous opioids (opioid
medications) differ vastly between acute and chronic pain.
2. Understanding pain as a disorder of the
nervous system
We can categorize pain as nociceptive (transmitted by nocicep-
tors), neuropathic (due to damaged nerves), or inflammatory
(produced by inflammatory mediators). In each case, we perceive
of a process occurring in the periphery that incites pain and which
could be amenable to reversal as a means of reducing the pain.
This is the concept of pain that many clinicians and patients cling
to, partly because pain always feels as if it is in the periphery, and
partly because of the hope that peripheral causes of pain can be
treated. Although it is true that indeed, many pain conditions do
have reversible peripheral causes, it is becoming increasingly clear
that the most refractory, perplexing, prolonged, and treatment-
resistance pain conditions may not.3 This realization, which is now
supported by copious scientific evidence, should alter the way we
approach the management of difficult pain problems.
Much chronic pain is successfully managed with either primary
disease control (eg, anti-inflammatory treatment of arthritis) or
targeted analgesics (eg, anticonvulsants or antidepressants for
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
Department of Anesthesiology and Pain Medicine, University of Washington School
of Medicine, Seattle, WA, United States
Address: Department of Anesthesiology and Pain Medicine, University of
Washington School of Medicine, Box 356540, Seattle, WA 98195-6560, United
States. Tel.: (206) 543 2568; fax: (206) 543 2958. E-mail address: jcb12@uw.edu (J.
C. Ballantyne).
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http://dx.doi.org/10.1097/j.pain.0000000000001270
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Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
neuropathic pain). Regardless, pain will persist in some individuals
and not in others. Persistent painful stimulation induces sensitiza-
tion that can be counteracted by endogenous inhibitory control.
For many individuals, a balance develops between sensitization
and inhibition so that chronic pain, even if pain generators are
present, does not become a persistent and overwhelming
problem. Those individuals in whom chronic pain does become
a persistent and overwhelming problem could be especially prone
to sensitization, lacking in endogenous inhibitory control, or both.
2.1. Propensity to sensitization
Stimulation of nociceptors can trigger a reversible increase in
excitability and synaptic efficacy in pain pathways throughout the
nervous system, a phenomenon termed “central sensitization.”
Such induction of excitability shifts the sensitivity of the nervous
system so that painful stimulation becomes more painful (hyper-
algesia), and normally non-noxious stimulation becomes noxious
(allodynia). The exact molecular mechanisms for central sensiti-
zation remain obscure,6,22,49,90,94 but it becomes increasingly
clear from clinical studies that for a range of pain states, which
includes fibromyalgia, osteoarthritis, temporomandibular joint
disorders, generalized musculoskeletal pain, low back pain,
visceral pain, and postsurgical pain, a propensity to central
sensitization plays an important role in the development of
pain.124 In affected individuals, normally nonpainful or minimally
painful activity incites pain that is severe enough for affected
individuals to seek medical help.102,124 Although central sensi-
tization is reversible, the increase in pain sensitivity induced in
these individuals on a chronic basis makes their central
sensitization de facto a chronic state of the nervous system.
2.2. Deficiency in endogenous inhibition
Since it was first inferred by researchers in the 1950s,18,68,119
descending inhibition of pain and its mechanisms are now well
established.17,19,58,59 Pain processing pathways in the brain are
widespread and contribute to a “multisensory salience network”
(embracing both nociceptive and non-nociceptive input) that is
involved in estimating the saliency or relevance of its input. The
network processes stimuli that alert the organism to danger, or
incite reward to reinforce behaviors that are advantageous to
survival.6,30,45,69 Thus, the network, with its connections within
reward and limbic systems, serves to determine what is perceived
(pain or pleasure) according to survival values. It is perhaps no
surprise that the endogenous opioid system plays a key role in
these functions, in the balancing of pain and reward, and in the
affective dimension of pain.72,86
Building on the idea that perceived pain is less a simple
reflection of nociceptive input than a complex product of
calculations of the motivational value of pain, one can begin to
see the importance of the brain in determining what is perceived
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as pain. Because the brain is capable of processing nociceptive
input so that no pain is perceived (and may do this in normal
individuals, despite the existence of peripheral pain generators), is
chronic pain then a disease of the brain? In fact, accumulating
evidence from functional magnetic resonance imaging studies
suggests that the brain undergoes extensive change in chronic
pain states and differs markedly from the brain with prolonged
acute pain.4,6,31,110 The conscious perception of pain depends
on the conversion of nociception to perception in the mesolimbic
system. As chronic pain develops, learning-based synaptic
reorganization causes the thresholds for conversion from
nociception to perception to shift.3,5,8,47 Such learning-based
synaptic reorganization is similar to that occurring in the
development addiction.91,115,116 The model that has been
proposed on the basis of functional magnetic resonance imaging
studies is one where chronic pain is primarily a neurological
disorder, nociceptive input is less important, and brain properties
are the primary determinants of risk of chronic pain.4,6,7,32,110–112
Underlying this model is the assumption that genetic or
environmental factors embedded in the limbic system account
for differences between individuals in the way pain is processed.7
Chronic pain is thereby seen as a learned state and a maladaptive
neuropathological disease largely independent of nociceptive
input (Table 1).
3. Stress, endogenous opioid dysfunction, and
chronic pain
Stress responses exist to maintain homeostasis and improve
survival. Stress responses may occur through attempts to
balance punishment and reward within the pain salience network,
as previously described.19,58,59,86 They may also serve to balance
stress hormone–induced arousal and avoidance behaviors, with
antiarousal mechanisms, many of which are opioid medi-
ated.82,88,99,100,113 Corticotrophin-releasing factor (CRF) is
a brain neuromodulator that coordinates autonomic, behavioral,
and cognitive responses to stress. By its effects in the locus
coeruleus, a noradrenergic brain stem nucleus that mediates
physiological responses to stress and pain, this hormone helps
increase arousal and attention. Endogenous opioids are also
active in the locus coeruleus, having the opposite effects to CRF,
and are important for helping the organism recover after the
stressor disappears. The counteraction between CRF and
endogenous opioids works well to balance arousal and anti-
arousal during acute stress. However, with repeated stress,
particularly early social rejection or abuse, opioid tone increases
and becomes dominant. This increased opioid tone means that
individuals who have been subjected to repeated stress may
develop something similar to tolerance to exogenous opioids. It is
proposed that chronic stress thus induces a state of endogenous
opioid-induced tolerance and dependence similar to chronic
exposure to opioids where tolerance to opioid analgesics is
Table 1
Proposed pain and reward concepts and related terminology.
Pain terms Reward terms
Perceived pain (pain that is felt) Pleasure, hedonia, and euphoria (reward
that is felt)
Nociception, sometimes physiological Reward (not necessarily felt)
(not necessarily felt)
Persistent or pathological pain (a Addiction (a maladaptation of
maladaptation of a physiological state) a physiological state)
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com S25
increased, and attempts to avoid withdrawal may result in opioid
overuse.42,65,113,122 This is effectively a state of continuous
withdrawal, which could contribute to the development of pain
through withdrawal hyperalgesia. High-opioid tone also produces
a state of reward deficiency or anhedonia—a reduced capacity to
experience pleasure or indeed to experience the reward and
salience associated with pain relief. Such reward deficiency
would be similar to that well described in substance abus-
ers.97,108 This could contribute to the vulnerability of affected
individuals to develop comorbid pain, high-dose opioid use,
opioid abuse, depression, anxiety, and post-traumatic stress
disorder.6,20,38,42,66,70,71,73,120
High tonic levels of endogenous opioids also downregulate
m-opioid receptors on g-aminobutyric acid inhibitory neurons that
normally keep antinociceptive neurons switched off. Dysregula-
tion of the endogenous opioid system leads to less excitation of
antinociceptive brain regions by incoming noxious stimulation,
which becomes manifest as hyperalgesia and allodynia. Thus, the
patient with generalized pain lacks valuable pain inhibition.95 This
helps explain both the lack of efficacy of exogenous opioids and
the efficacy of the opioid antagonist naltrexone for generalized
pain conditions such as fibromyalgia.84,125
4. The brain on opioids
This discussion will be centered on the brain effects of long-term
opioid use when opioids are used for the treatment of pain. Short-term
or occasional opioid use may result in early brain changes, but what is
of greater interest here is the changes that arise with longer-term use.
Brain changes that arise in persons addicted to opioids have been
increasingly well elucidated.23,44,114 Although there is inevitable
overlap in brain changes between use for pain and addiction, the
focus here will be on brain changes arising from use for pain.
4.1. Central sensitization
It is believed that a propensity to develop central sensitization
underlies many chronic pain conditions, especially the conditions
we currently call centralized pain conditions, which include
fibromyalgia, musculoskeletal pain, chronic low back pain with no
pathoanatomic basis, jaw pain, headache, irritable bowel
syndrome, and pelvic pain. Neither the molecular changes
producing sensitization, nor the underlying genetic and environ-
mental factors, are fully understood. Nevertheless, recent
scientific exploration has revealed many similarities between
sensitization arising from noxious stimulation, and those arising
from opioid administration. This raises the question whether
despite their ability to provide symptom relief, opioids could in
some circumstances augment the sensitization in centralized
pain states, or any pain state where repeated or continuous
noxious stimulation is occurring.
For practical purposes, and for clinicians using opioids to treat
pain, opioid tolerance is the need to increase opioid dose to
achieve the same level of analgesia. However, that clinical end
point is produced not only by changes at the opioid receptor level,
but can also be produced by activation of pronociceptive systems
by opioids.2,41,76,101 Multiple cellular events are involved in the
pronociceptive adaptive response produced by opioid exposure,
and most of them are common to the pronociceptive processes
involved in the development and maintenance of chronic
pain.27,33,48,87,90,101,103 Existing data strongly support long-
term neuronal changes caused by opioid exposure, even short-
term exposure. This suggests that pain vulnerability may be
facilitated by opioid use.
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In addition to such neuronal changes, there is now abundant whereby no dose is enough, in other words, pain persists despite
evident that opioids can produce neuroinflammatory responses in repeated dose escalation (Fig. 1).
both the peripheral and central nervous system. Microglia-to- It is clear that people dependent on opioids do not simply
neuron signaling is known to play a key role in opioid-induced experience diminished opioid effects because of tolerance. The idea
tolerance and hyperalgesia, at least in part due to the release of that opioid dependency could be a state of continuous withdrawal is
proinflammatory cytokines and chemokines.67,80,83,123 Proinflam- suggested when intermittent emergence of mild withdrawal symp-
matory cytokines are believed to play a role in the generation and toms is seen in opioid-dependent patients, despite stable dosing.
enhancement of chronic muscle pain, including fibromyalgia.102 This dysfunction could be explained by the fact that these patients are
Both chronic pain and chronic opioids engage similar neuroimmune experiencing drug-opposite effects as long as drug administration
mechanisms in the brain and spinal cord, which contribute to pain continues. Moreover, this dysfunction could extend to their mood and
and negative affect. Moreover, both chronic pain and chronic ability to function socially.12,122 In this case, continuous withdrawal is
opioids promote neuroinflammation in limbic brain structures a drug effect, but it could exacerbate the continuous withdrawal that
contributing to negative affective states, which may increase the might occur if a patient has increased opioid tone as a consequence
propensity to opioid misuse in patients with chronic pain.22,109 of repeated stress described previously.20,113,122
It seems that long-term opioid-induced pronociceptive activity The importance of continuous withdrawal is brought into focus by
may persist long after cessation of opioid administration (latent pain the clinical presentation of patients doing badly with opioid therapy
sensitization).40,61,90 This is consistent with the idea that opioids of chronic pain. They report high levels of pain, despite high doses of
produce long-term alterations in pain sensitization, which facilitate opioid. Yet, they cannot be convinced that the opioid is not helping
the initiation and maintenance of the chronic pain state. Data because if they try to reduce their dose, the pain worsens, likely
support the critical role of microglia not only in opioid-induced because of withdrawal, but interpreted as needing opioid.
hyperalgesia and tolerance, but also in long-term pain sensitization Furthermore, in multiple studies, and according to anecdotal
observed after brief exposure to opioid. Opioids may also trigger experience, people who successfully stop their opioid treatment
epigenetic mechanisms that produce hyperalgesia and toler- report no change in pain, sometimes even an improvement, only
ance.93 Whether through cellular processes such as receptor a “lifting of the cloud” and “return of the old personality.”
trafficking, intracellular signaling, N-methyl-D-aspartate neuro-
transmission or epigenetic changes, opioid-induced neuroinflam-
4.3. Disruption of normal rewards and social functions
mation, or latent pain sensitization, opioid-induced tolerance and
hyperalgesia must be seen as potentially irreversible phenomena. Although this article does not set out to describe the brain
changes that arise with addiction, the risk that opioid treatment of
pain could lead to opioid addiction (more properly termed “opioid
4.2. Tolerance, dependence, and continuous withdrawal
use disorder”) cannot be ignored. It probably does not need to
Although many factors contribute to the development of persistent
pain, it seems that the most important of these is dysfunction of
endogenous inhibition of pain, in turn largely mediated by
endogenous opioids.102 This fact is highlighted when considering
that regardless of peripheral generation of pain, be it nociceptive,
neuropathic, or inflammatory, the pain that is actually perceived is
determined by central processes in the brain. Healthy individuals
can often suppress nociceptive input; for patients with chronic pain,
inability to achieve such suppression may underlie their propensity
to progress to the chronic pain state. Many of the processes
underlying failed pain inhibition have already been discussed. What
follows is a discussion of the ways in which the brain adapts to
chronic opioid administration, and the ways in which these
adaptations may impair natural pain inhibition.
Opioid tolerance and dependence have been described in
detail elsewhere.9,12 What is important in the present context is
the relationship between tolerance and dependence. Tolerance
may be a receptor phenomenon (nonassociative) or a psycho-
logical phenomenon (associative).53,104,117 The latter means that
independent of changes in receptor function brought about by
continuous exposure to opioid drugs, psychological factors such
as anxiety, exposure to stress, or changes in circumstance, can
result in an increase (or in some cases, a decrease) in tolerance.
Any increase in tolerance that is not compensated for with a dose
escalation will result in withdrawal, an unpleasant experience
comprising physical symptoms (nausea, abdominal cramps,
piloerection, dilated pupils, agitation, and tachycardia), anhedo-
Figure 1. Tolerance and dependence work together. Both tolerance and
nia, and importantly, hyperalgesia. Dependence, and the dependence are adaptations to continuous opioid use and they cannot be
symptoms of withdrawal, are powerful drivers of opioid seeking separated. If tolerance arises, whether because of psychological or
for all persons using opioids continuously, not only people who pharmacological factors or both, withdrawal symptoms, including a worsening
have developed opioid use disorder.23,51 Tolerance, depen- of pain, will persist unless the opioid dose is increased. Each dose escalation
will restore analgesics efficacy, but multiple dose escalations may be needed,
dence, and opioid seeking in turn drive up opioid doses. leading to the distressing but all too common state in which no dose is enough.
Ultimately, patients taking opioids for pain can enter a state

Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
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state that addiction is a miserable state that seriously impairs the
affected individual’s ability to function in society, to have normal
social relations, and to work. In the natural state, endogenous
opioid systems balance punishment (perceived pain) and reward
(perceived pleasure) in pain and reward centers in the brain, which
are closely aligned. Pain relief is rewarding; damaged reward is
painful. Chronic pain and addiction are both learned states and
represent dysfunction of the normal adaptations that regulate
survival behaviors including adjustments in pain levels, feeding,
socialization, and sex (Table 1). A likely majority of individuals do
not become addicted when using opioids for the treatment of
chronic pain. Assessment of addiction rates for opioid-treated
chronic pain has proven difficult because there is little consensus
on addiction definitions and terminology in the case of analgesic
use, with the result that recent estimates vary widely according to
the definitions used, but also according to the type of study and the
population under study.21,78,118 It would seem from population
data that at least 75% of those taking opioids for the treatment of
chronic pain do not become addicted. At the same time, it must be
acknowledged that there are several factors that suggest a higher
risk of addiction for opioid-treated chronic pain patients than for the
general population.1,12,38,42,43,56,66,77,97 Patients with chronic pain,
especially those with centralized pain states, tend to have
psychiatric comorbidities common to both chronic pain and
addiction. As already described, patients with centralized pain
may have high-opioid tone with continuous withdrawal, as well as
reward deficiencies, all of which put them at risk of craving
opioids.36,37,64,85,89,96,98,105,121 These factors are compounded by
being on opioids because exogenous opioids exacerbate contin-
uous withdrawal, and overwhelm natural endogenous opioid
functioning to the extent that the opioid drug is necessary to
achieve pain relief and other rewards.
Although the development of addiction may not be inevitable for
patients with chronic pain taking opioids, the development of
dependence is inevitable for all persons taking opioids continuously
and long term.13 Many of the neuroadaptations that arise with
continuous opioid use occur with dependence as well as with
addiction, except the secondary learning that leads to synaptic
reorganization and permanent brain changes, which will differ
between dependence and addiction because behaviorally, relief
seeking differs markedly from drug seeking.44,51–53 The main
difference between dependence and addiction is the lack of craving
and compulsive use in the former (although craving and compulsive
use may actually emerge in apparently nonaddicted patients if their
opioid treatment is stopped abruptly). In other respects, however,
dependence, and the neuroadaptations underlying it, is similar to
addiction and a possible precursor to addiction.9,13 Dependence is
manifest as withdrawal, and possibly continuous withdrawal, which
drives opioid seeking. Dependence on opioids is also associated
with reward deficiencies. Just as for the addicted person, normal
endogenous opioid functions are overwhelmed by the opioid drug,
and it becomes more difficult to muster natural pain relief and
rewards, so increasing the likelihood of needing opioids. What has
become increasingly clear from U.S. opioid epidemic is that there is
a high incidence of social dysfunction and work disability attributable
to opioid use that is higher than the incidence of addiction.26,57 We
are learning that these deleterious effects on essential human
functions are associated not just with addiction and pain, but with
continuous long-term opioid use itself.
5. Summary
Caution in using or prescribing opioids long term has existed for
centuries. Such caution has been based on the association of
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com S27
long-term opioid use with addiction. In the 20th century, it was
suggested that the existence of pain protected against addiction,
and that fear of addiction was unwarranted when treating chronic
pain. A consequence of this change in thinking was that opioid
treatment of chronic pain became much more commonplace in
many countries, particularly in the United States. This expansion of
opioid prescribing did not have entirely happy results, and in fact in
the United States, it led to an epidemic of prescription opioid
abuse. The reasons for the U.S. prescription opioid epidemic are
many and complex, and were not fully explored in this article, other
than to note that some but not all the abuse and death arises from
diverted opioid and not from patients with pain. What is of interest
here is the analgesic efficacy and safety of long-term opioid
treatment. This article has explored new knowledge about how
chronic pain develops, and how exogenous opioids, despite being
largely effective for symptom relief, can actually worsen the
underlying pain processes. Much has been learned from the
outcomes data that have arisen out of widespread prescribing of
opioids for chronic pain over the past few decades; and much has
been learned about how that clinical experience informs, and is
informed by, what is being revealed in the laboratory. Understand-
ing how chronic pain differs from short-lived pain is a critical first
step towards understanding that opioid treatment can be highly
effective and relatively safe for the treatment of severe short-lived
pain, yet when it is used to treat chronic pain, it can have limited
efficacy, significant safety concerns, and poor outcomes.
Early evidence in the 1980s and 1990s supporting efficacy and
safety for chronic opioid therapy consisted of randomized
controlled trials plus some observational studies. Both types of
studies were conducted over limited time spans, recruited select
populations, and used dose restrictions.10,11 These studies were
largely positive and largely supportive of chronic opioid treatment.
It was not until later that population studies began to give rise to
concern about the efficacy and safety of chronic opioid
therapy.28,29 The first long-term (12 months) pragmatic random-
ized trial of chronic opioid therapy published this year finds worse
pain and adverse effects for opioid-treated patients with low back
pain, hip, and knee arthritis compared with non–opioid-treated
matched controls.55 An important lesson learned from the
population studies is that problematic opioid use, including loss
of control over use, opioid use disorder, accidental overdose,
suicide, and analgesic failure, is more likely to arise in individuals
with psychiatric comorbidities.24,36,37,64,85,89,97,98,105,121 There
are also individuals who are likely to escalate to high doses, which
increases these risks. This link between high-dose usage, poor
outcomes, and multiple pain comorbidities has been termed
“adverse selection.”106 It seems that the patients who eventually
have difficulty in controlling their opioid use and end up on high
and risky opioid doses (often made more dangerous by
concomitant use of other central nervous system depressants)
are a self-selected group of patients with preexisting risk. We
have tended to assume that it is the high doses that are risky, but it
is equally possible that it is underlying risk factors and the
behaviors that are risky.14
Chronic pain is not the same as acute or short-lived pain, and
a key factor in the development of chronic pain, or risk of chronic
pain, is stress. This is particularly true of chronic refractory,
nonresponsive pain. Stress increases vulnerability to a host of
stress-induced illnesses, including chronic pain, and the disrup-
tion of normal endogenous opioid function is a key factor in the
long-term effects of stress. Because endogenous opioids play
a central role in social functioning for
humans,12,15,16,25,34,35,46,54,60,62,74,75,79,81,107 not only does
social rejection and other abuse frequently underlie chronic pain
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J.C. Ballantyne 159 (2018) S24–S30
and associated disorders, the resulting disruption of endogenous
opioid function then perpetuates the risk. The idea that opioid
tone is increased in these high-risk individuals suggests that they
hunger for exogenous opioids, often get relief only from
exogenous opioids, yet have inherent high risk of developing an
opioid use disorder. Unfortunately, when these high-risk individ-
uals become dependent on opioids, which they inevitably do if
they take opioids continuously and long term, one result is that
their social functioning deteriorates even further.26,57
What begins to emerge from population data and an improved
understanding of chronic pain is that high-risk individuals may
account for the majority of the poor outcomes and the alarming
statistics that have forced a reexamination of chronic opioid
treatment. It is unfortunate that we do not have any way of
measuring how many, and which, people use opioids safely and
with good effect, but anecdotal reports still suggest that there are
long-term opioid treatment successes. Reluctance to abandon
chronic opioid treatment altogether is based on these successes,
and on the hope that a combination of pharmacological, genetic,
and molecular research will produce better and safer solutions.
One promising avenue of research is based on the idea of biased
ligands that can target analgesic pathways (the Gi/o signaling
proteins) and spare adverse effects pathways (the ß-arrestin
signaling proteins).50,63,92 A separate line of research involves the
role of buprenorphine and other kappa antagonists, which have
already proven useful in the treatment of chronic pain comorbid-
ities (depression and addiction), as well as pain itself.39,65,66
Regardless, present knowledge suggests that traditional opioids
have serious safety concerns and limited long-term efficacy for
the majority of those who were selected for chronic treatment
before present-day concerns were raised. Understanding exog-
enous opioid risks and the factors that contribute to them will go
a long way towards optimizing both pain treatment and the role of
exogenous opioids.
Conflict of interest statement
The author has no conflict of interest to declare.
Acknowledgments
Much of the groundwork for this article was completed in
collaboration with Mark D. Sullivan, University of Washington,
Seattle, WA, United States. No technical support was needed. No
financial support was given.
Article history:
Received 9 February 2018
Received in revised form 24 April 2018
Accepted 25 April 2018
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